Certain pyrrolopyrimidine compounds are modulators of protein kinases and are therefore useful in protein kinase-mediated diseases, including cancer and chronic inflammation. A particular kinase of interest is epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans). This kinase is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). EGFR is reportedly deregulated in most solid tumor types, such as lung cancer, breast cancer, and brain tumors. Resistance to known therapies develops due to the presence of a mutation of T790M, which is the gatekeeper of EGFR. Certain pyrrolopyrimidine compounds show selective inhibition of the T790M-mutated EGFR inhibitor relative to the wild type EGFR. It is desirable to develop a more efficient EGFR inhibitor that will target substantially the mutated EGFR over the wild type protein. Other protein kinases that are useful targets for small molecule pharmaceuticals include B lymphoid tyrosine kinase (BLK), janus kinase 1 (JAK1), bone marrow kinase on the X chromosome (BMX/ETK), Bruton's tyrosine kinase (BTK), janus kinase 2 (JAK2), janus kinase 3 (JAK3), tyrosine kinase expressed in hepatocellular carcinoma (TEC), resting lymphocyte kinase (TXK, also known as RLK), FMS-like tyrosine kinase 3 (FLT3), and FLT3 (D835Y). Such compounds are described in PCT Publ. No. WO2014/025486.
An efficient method of making such pyrrolopyrimidine kinase inhibitors is needed to allow for clinical testing and commercial use. Such methods, and intermediates useful for the preparation of such compounds, are described herein. Certain salt forms and polymorphs of said compounds are also described.
Certain pyrrolopyrimidine compounds, including N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide and pharmaceutically acceptable salts thereof, are useful in treating tumors and related diseases related to the dysregulation of kinases such as those described herein (including, but not limited to, EGFR (including HER), Alk, and PDGFR pathways). See, e.g., U.S. Pat. No. 8,685,998 B2.
In general, drug stability is an important consideration in the design, manufacture, and storage of pharmaceutical compositions. Drug products that lack stability can form degradation products that can cause undesirable side effects or, in some cases, can cause a decrease in the efficacy and bioavailability of the drug substance itself, making it difficult for physicians to prescribe consistent and effective doses. Therefore, pharmaceutical compositions containing active therapeutic agents, such as those described herein, including N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide and pharmaceutically acceptable salts thereof, that have quick release characteristics, excellent stability, extensive adaptability, and medicinal significance are needed. Described herein are such pharmaceutical compositions.